4-Hydroxy-2-nonenal induces endothelial cell injury via PKCdelta and biphasic JNK activation

Abstract

4-Hydroxy-2-nonenal (4-HNE), a major product generated during oxidative stress, exhibits cytotoxic effects; however, the mechanisms of 4-HNE-induced endothelial cell injury are not well defined. To explore this issue, we examined how 4-HNE damages human umbilical vein endothelial cells (HUVECs) and found that 4-HNE induced biphasic activation of c-Jun N-terminal kinase (JNK). Both pre- and post-treatment of HUVECs with SP600125, a specific JNK inhibitor, significantly suppressed the cytotoxic effects of 4-HNE. Inhibition of protein kinase Cd (PKCd), which was also phosphorylated by 4-HNE, reduced endothelial cell injury as well as late-phase JNK phosphorylation elicited by 4-HNE. Inversely, pre-treatment of HUVECs with SP600125 suppressed PKCd activation. Taken together, these results support the concept that 4-HNE induces vascular endothelial cell injury by the interaction between biphasic JNK activation and the PKCd pathway.